tuneTypical Dose
800-1600
Supplement
S-adenosylmethionine
S-adenosyl-L-methionine
Evidence TierBWADA NOT PROHIBITED
watchEffect Window
2-12 weeks in trials. Practical evaluation by week 6-8.
check_circleCompliance
WADA NOT PROHIBITED
Overview
Clinical Summary
S-adenosylmethionine is a small molecule, salt, or polymer used for targeted metabolic or digestive effects. It is used to influence specific pathways rather than general nutrition.
Evidence varies widely by compound. Some have controlled human data for specific outcomes such as lipid markers, glycemic response, or symptom relief, while others are supported mainly by mechanistic studies. Minority uses include inflammation modulation and antioxidant effects. Dose, formulation, and safety constraints often determine whether measurable benefits occur.
Methyl-donor support of one-carbon and monoamine-related pathways may underlie antidepressant effects.
Outcomes
What This Is Expected To Influence
Primary Outcomes
- Reduction in depressive symptoms (strongest as monotherapy)
- Uncertain additive effect with concurrent antidepressants
Secondary Outcomes
- Mixed/limited evidence in osteoarthritis
- Limited clinical utility signal in chronic liver disease
Safety
Contraindications and Interactions
Contraindications
- Bipolar disorder or prior antidepressant-induced mania without psychiatric supervision
- Active manic/hypomanic or psychotic symptoms
- Pregnancy or lactation without specialist input
- Known intolerance to SAMe formulations
Side effects
- Constipation
- Abdominal pain
- Headache
- Nausea
- Diarrhea
- Flatulence
- Anxiety
- Activation/restlessness
- Insomnia
- Decreased appetite
Interactions
- SSRIs/SNRIs/MAOIs/tricyclics and other serotonergic agents (serotonin-toxicity caution)
- Serotonergic supplements (5-HTP, tryptophan, St. John's wort)
- Linezolid or other MAOI-like agents (increased serotonin-toxicity risk)
- Levodopa (possible reduced effectiveness due to methyl-donor effects)
- Complex psychotropic combinations, including antipsychotics (close monitoring required)
Avoid if
- Bipolar-spectrum risk without psychiatric follow-up
- Pregnancy or lactation without clinician input (insufficient high-quality safety data)
- Users unable to monitor mood activation closely
Evidence
Study-level References
s-adenosyl-methionine-SRC-001Systematic review and meta-analysis of RCTs.
Sourceopen_in_newLimveeraprajak N, et al. Efficacy and acceptability of S-adenosyl-L-methionine (SAMe) for depressed patients: A systematic review and meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry. 2024;132:110985. doi:10.1016/j.pnpbp.2024.110985. PMID:38423354.
Population: 23 trials, 2183 participants with depression.
Dose protocol: SAMe versus placebo, adjunctive versus placebo+AD, and SAMe versus AD comparators.
Key findings: Monotherapy superior to placebo. Adjunctive/comparator effects less clear.
Notes: Moderate heterogeneity across trial designs and populations.
Paper content
Monotherapy superior to placebo; adjunctive/comparator effects less clear.
s-adenosyl-methionine-SRC-002Systematic review and meta-analysis.
Sourceopen_in_newPeng TR, et al. S-Adenosylmethionine (SAMe) as an adjuvant therapy for patients with depression: An updated systematic review and meta-analysis. Gen Hosp Psychiatry. 2024;86:118-126. doi:10.1016/j.genhosppsych.2024.01.001. PMID:38199136.
Population: 14 trials, 1522 participants with MDD.
Dose protocol: 200-3200 mg/day, 2-12 week studies.
Key findings: No significant differences in several pooled comparisons.
Notes: Wide dose variation and limited study counts per comparison.
Paper content
No significant differences in several pooled comparisons.
s-adenosyl-methionine-SRC-003Cochrane systematic review.
Sourceopen_in_newGalizia I, et al. S-adenosyl methionine (SAMe) for depression in adults. Cochrane Database Syst Rev. 2016;(10):CD011286. doi:10.1002/14651858.CD011286.pub2. PMID:27727432.
Population: 8 trials, 934 adults with depression.
Dose protocol: Monotherapy and adjunctive use, oral/parenteral regimens.
Key findings: Inconclusive overall. Possible adjunctive signal in one small study.
Notes: Evidence graded low to very low for several outcomes.
Paper content
Inconclusive overall; possible adjunctive signal in one small study.
s-adenosyl-methionine-SRC-004Double-blind randomized controlled trial.
Sourceopen_in_newSarris J, et al. Adjunctive S-adenosylmethionine (SAMe) in treating non-remittent major depressive disorder: An 8-week double-blind, randomized, controlled trial. Eur Neuropsychopharmacol. 2018;28(10):1126-1136. doi:10.1016/j.euroneuro.2018.07.098. PMID:30115553.
Population: 107 treatment non-remittent outpatients with MDD.
Dose protocol: 800 mg/day adjunctive SAMe versus placebo for 8 weeks.
Key findings: No significant between-group efficacy difference. One serotonin syndrome-like case reported.
Notes: High placebo response. Limited power for subgroup conclusions.
Paper content
No significant between-group efficacy difference; one serotonin syndrome-like case reported.
s-adenosyl-methionine-SRC-005Cochrane systematic review.
Sourceopen_in_newRutjes AW, et al. S-Adenosylmethionine for osteoarthritis of the knee or hip. Cochrane Database Syst Rev. 2009;(4):CD007321. doi:10.1002/14651858.CD007321.pub2. PMID:19821403.
Population: 4 placebo-controlled trials, 656 patients with knee/hip OA.
Dose protocol: Variable SAMe dosing, placebo comparators.
Key findings: Small uncertain effects. Routine use not advised.
Notes: Small/older trials with poor reporting quality.
Paper content
Small uncertain effects; routine use not advised.
s-adenosyl-methionine-SRC-006Systematic review and meta-analysis.
Sourceopen_in_newGuo T, et al. S-adenosyl-L-methionine for the treatment of chronic liver disease: a systematic review and meta-analysis. PLoS One. 2015;10(3):e0122124. doi:10.1371/journal.pone.0122124. PMID:25774783.
Population: 12 RCT datasets (705 patients) with chronic liver disease.
Dose protocol: Variable SAMe protocols versus placebo/active comparators.
Key findings: Some lab-marker improvement, limited overall clinical value.
Notes: Mixed populations and variable comparators reduce direct applicability.
Paper content
Some lab-marker improvement, limited overall clinical value.
s-adenosyl-methionine-SRC-007Case report.
Sourceopen_in_newAbeysundera H, Gill R. Possible SAMe-induced mania. BMJ Case Rep. 2018;2018:bcr2018224338. doi:10.1136/bcr-2018-224338. PMID:29950497.
Population: Mania with psychotic features during SAMe plus SSRI use.
Dose protocol: Concomitant serotonergic exposure.
Key findings: Supports plausible mania risk signal in vulnerable users.
Notes: Single-case evidence, not incidence estimate.
Paper content
Supports plausible mania risk signal in vulnerable users.
s-adenosyl-methionine-SRC-008Small pharmacokinetic/safety trial.
Sourceopen_in_newGoren JL, et al. Bioavailability and lack of toxicity of S-adenosyl-L-methionine (SAMe) in humans. Pharmacotherapy. 2004;24(11):1501-1507. doi:10.1592/phco.24.16.1501.50943. PMID:15537554.
Population: 15 healthy volunteers over 4 weeks.
Dose protocol: Oral SAMe titrated to 1600 mg/day.
Key findings: Bioavailable and generally tolerated. One transient mixed manic episode.
Notes: Small open-label sample.
Paper content
Bioavailable and generally tolerated; one transient mixed manic episode.
s-adenosyl-methionine-SRC-009Systematic review and meta-analysis.
Sourceopen_in_newUrata M, Sakurai H, Ueno F, et al. Efficacy of pharmacological interventions in milder depression: a systematic review and meta-analysis. Neuropsychopharmacol Rep. 2025;45(1):e70008. doi:10.1002/npr2.70008. PMID:40014460.
Population: Adults with milder forms of depression across multiple pharmacological intervention trials.
Dose protocol: Meta-analysis of pharmacological interventions for milder depression including SAMe.
Key findings: SAMe did not produce significant improvements relative to placebo for milder depression.
Notes: Tempers positive signals from earlier meta-analyses by showing SAMe may not extend to milder presentations.
Paper content
This systematic review and meta-analysis examined the efficacy of multiple pharmacological interventions for milder forms of depression. Among the agents assessed, SAMe (S-adenosylmethionine) did not produce significant improvements relative to placebo. The finding adds nuance to the SAMe evidence base by suggesting that its antidepressant signal, while supported in some earlier meta-analyses for broader depression populations, may not extend reliably to milder presentations. The study is useful for calibrating expectations around SAMe monotherapy, particularly in patients with subthreshold or mild depressive symptoms.